Flexibility to build a tailored treatment regimen with dolutegravir at the core

About Tivicay

TIVICAY—the flexibility to build a regimen with dolutegravir at the core

Rapid and sustained efficacy1,6-12

High barrier to resistance1,6-12

Booster-free dosing1,6-12

Indication and Dosing

TIVICAY is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-infected adults, adolescents and children aged 6 years and over, weighing at least 15kg.1*

Naive Patient infected with HIV-1 without documented or clinically suspected resistance to the integrase class. The recommended dose of dolutegravir is 50 mg (one tablet) orally once daily. Tivicay should be administered twice daily in this population when co-adminstered with some medicines (e.g. efavirenz, nevirapine, ritonavir or rifampicin)

Patients infected with HIV-1 with resistance to the integrase class The recommended dose of dolutegravir is 50 mg (one tablet) orally twice daily. In the presence of documented resistance that includes Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T, L741, modelling suggests that an increased dose may be considered for patients with limited treatment options (less than 2 active agents) due to advanced multi class resistance.1

*Must be taken in combination with other antiretroviral agents.1

TIVICAY is available in 3 tablet strengths (10 mg, 25 mg and 50 mg)

Dosed according to weight of the patients (≥6 years of age, weighing at least 15kg)*1

Once daily in patients without documented or clinically suspected resistance to the integrase class

Dolutegravir should not be used with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir in INI-resistant patients.

Lopinavir/Ritonavir + Etravirine

Dolutegravir ↔

AUC ↑ 11 %

Cmax ↑ 7 %

Cτ ↑ 28 %

LPV ↔

RTV ↔

No dose adjustment is necessary.

Darunavir/Ritonavir + Etravirine

Dolutegravir ↓

AUC ↓ 25 %

Cmax ↓ 12 %

Cτ ↓ 36 %

DRV ↔

RTV ↔

No dose adjustment is necessary.

Efavirenz

Dolutegravir ↓

AUC ↓ 57 %

Cmax ↓ 39 %

Cτ ↓ 75 %

Efavirenz ↔ (historical controls)

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz.

In the presence of integrase class resistance alternative combinations that do not include efavirenz should be considered.

Nevirapine

Dolutegravir ↓

(Not studied, a similar reduction in exposure as observed with efavirenz is expected, due to induction).

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine.

In paediatric patients the weight-based once daily dose should be administered twice daily. In the presence of integrase class resistance alternative combinations that do not include nevirapine should be considered

Rilpivirine

Dolutegravir ↔

AUC ↑ 12 %

Cmax ↑ 13 %

Cτ ↑ 22 %

Rilpivirin ↔

No dose adjustment is necessary.

HIV-1 Antiviral Agents

NRTI

Medical Products by therapeutic areas

Interaction Geometric mean change (%)

Recommendations concerning co-administration

Tenofovir

Dolutegravir ↔

AUC ↑ 1 %

Cmax ↓ 3 %

Cτ ↓ 8 %

Tenofovir ↔

No dose adjustment is necessary.

HIV-1 Antiviral Agents

Protease Inhibitors

Medical Products by therapeutic areas

Interaction Geometric mean change (%)

Recommendations concerning co-administration

Atazanavir

Dolutegravir ↑

AUC ↑ 91 %

Cmax ↑ 50 %

Cτ ↑ 180 %

Atazanavir ↔ (historical controls)

(inhibition of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Tivicay should not be dosed higher than 50 mg twice daily in combination with atazanavir due to lack of data

Atazanavir/Ritonavir

Dolutegravir ↑

AUC ↑ 62 %

Cmax ↑ 34 %

Cτ ↑ 121 %

Atazanavir ↔

Ritonavir ↔

(inhibition of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Tivicay should not be dosed higher than 50 mg twice daily in combination with atazanavir due to lack of data

Tipranavir/Ritonavir (TPV+RTV)

Dolutegravir ↓

AUC ↓ 59 %

Cmax ↓ 47 %

Cτ ↓ 76 %

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with tipranavir/ritonavir the absence of integrase class resistance.

In the presence of integrase class resistance this combination should be avoided.

Fosamprenavir/Ritonavir (FPV+RTV)

Dolutegravir ↓

AUC ↓ 35 %

Cmax ↓ 24 %

Cτ ↓ 49 %

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary in the absence of integrase class resistance.

In the presence of integrase class resistance alternative combinations that do not include fosamprenavir/ritonavir should be considered.

Nelfinavir

Dolutegravir ↔

(Not studied)

No dose adjustment is necessary.

Darunavir/Ritonavir

Dolutegravir ↓

AUC ↓ 22 %

Cmax ↓ 11 %

C24 ↓ 38 %

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Lopinavir/Ritonavir

Dolutegravir ↔

AUC ↓ 4 %

Cmax↔ 0 %

C24 ↓ 6 %

No dose adjustment is necessary.

Other Antiviral agents

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Daclatasvir

Dolutegravir ↔

AUC ↑ 33 %

Cmax ↑ 29 %

Cτ ↑ 45 %

Daclatasvir ↔

Daclatasvir did not change dolutegravir plasma concentration to a clinically relevant extent.

Dolutegravir did not change daclatasvir plasma concentration.

No dose adjustment is necessary.

No clinically significant interaction expected.

Elbasvir / Grazoprevir

AUC ↑ 16%

Cmax ↑ 22%

Ctrough 14%

Coadministration of mutliple doses of elbasvir / grazoprevir and dolutegravir had no clinically significant effect on the pharmacokinetics of grazoprevir, elbasvir or dolutegravir.

No dose adjustments are required. (In 12 subjects).

No clinically significant interaction expected.

Ombitasvir / Paritaprevir/r + Dasabuvir

Dolutegravir ↑ 22-38%

Coadministration of ombitasvir / paritaprevir / ritonavir + dasabuvir and doutegravir had no clinically significant effect on the pharamcokinetics of ombitasvir, paritaprevoe, ritonavir, dasabuvir or dolutegravir.

No dose adjustment is required.

(In 12 HIV/HCV-negative subjects).

No clinically significant interaction expected.

Ribavirin

Coadministration has not been studied

Based on metabolism and clearance a clinically significant interaction is unlikely.

Simeprevir

Coadministration has not been studied

Based on metabolism and clearance a clinically significant interaction is unlikely.

Sofosbuvir

Coadministration has not been studied

Based on metabolism and clearance a clinically significant interaction is unlikely.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Dofetilide

Dofetilide ↑

(Not studied, potential increase via inhibition of OCT2 transporter)

Dolutegravir and dofetilide co-administration is contraindicated due to potential life-threatening toxicity caused by high dofetilide concentrations.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Carbamazepine

Dolutegravir ↓

AUC ↓ 49 %

Cmax ↓ 33 %

Cτ ↓ 73 %

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with carbamazepine. In paediatric patients the weight-based once daily dose should be administered twice daily.

Alternatives to carbamazepine should be used where possible for INI resistant patients.

Oxcarbazepine

Phenytoin

Phenobarbital

Dolutegravir ↓

(Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected)

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with these metabolic inducers. In paediatric patients the weight-based once daily dose should be administered twice daily.

Alternative combinations that do not include these metabolic inducers should be used where possible in INI-resistant patients.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Ketoconazole

Fluconazole

Itraconazole

Posaconazole

Voriconazole

Dolutegravir ↔

(Not studied)

No dose adjustment is necessary. Based on data from other CYP3A4 inhibitors, a marked increase is not expected.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

St. John's wort

Dolutegravir ↓

(Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected)

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with St. John's wort. In paediatric patients the weight-based once daily dose should be administered twice daily.

Alternative combinations that do not include St. John's wort should be used where possible in INI-resistant patients.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Magnesium/

aluminium-containing antacid

Dolutegravir ↓

AUC ↓ 74 %

Cmax ↓ 72 %

(Complex binding to polyvalent ions)

Magnesium/ aluminium-containing antacid should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).

Calcium supplements

Dolutegravir ↓

AUC ↓ 39 %

Cmax ↓ 37 %

C24 ↓ 39 %

(Complex binding to polyvalent ions)

Calcium supplements, iron supplements or multivitamins should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).

Iron supplements

Dolutegravir ↓

AUC ↓ 54 %

Cmax ↓ 57 %

C24 ↓ 56 %

(Complex binding to polyvalent ions)

Multivitamin

Dolutegravir ↓

AUC ↓ 33 %

Cmax ↓ 35 %

C24 ↓ 32 %

(Complex binding to polyvalent ions)

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Prednisone

Dolutegravir ↔

AUC ↑ 11 %

Cmax ↑ 6 %

Cτ ↑ 17 %

No dose adjustment is necessary.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Metformin

Metformin ↑

When co-administered with dolutegravir 50mg once daily:

Metformin

AUC ↑ 79 %

Cmax ↑ 66 %

When co-administered with dolutegravir 50mg twice daily:

Metformin

AUC ↑ 145 %

Cmax ↑ 111 %

A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control.

In patients with moderate renal impairment a dose adjustment of metformin should be considered when coadministered with dolutegravir, because of the increased risk for lactic acidosis in patients with moderate renal impairment due to increased metformin concentration.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Rifampicin

Dolutegravir ↓

AUC ↓ 54 %

Cmax ↓ 43 %

Cτ ↓ 72 %

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin in the absence of integrase class resistance.

In the presence of integrase class resistance this combination should be avoided.